Signaling #9 Flashcards
What should you know about GPCR signaling by the end of the lecture?
Different ways in which GPCR signaling stops and the process of GPCR desensitization and internalization
Includes the role of β-arrestin as an adaptor molecule in GPCR desensitization.
What is angioedema?
Swelling similar to hives, but occurring under the skin instead of on the surface
Hereditary Angioedema (C1-INH-HAE) is a rare condition affecting ~6,000 people in the US.
What is the role of GRK2 in angioedema?
Decreased GRK2 levels are associated with pathologies like angioedema
GRK2 plays a pivotal role in the regulation of vascular permeability.
What is the midterm exam format?
Multiple choice (~20) and 2 short answer questions, lasting 50 minutes
Scheduled for Monday, February 10th, from 10:30 to 11:20.
What initiates GPCR desensitization?
Activation of the receptor by ligand binding
This process requires the receptor to be activated.
Name two key players in GPCR desensitization.
- 2nd messenger dependent protein kinases (e.g., PKA, PKC)
- G protein coupled R kinases (GRKs)
These components phosphorylate the ligand-bound GPCR.
What is the effect of PKA and PKC phosphorylation on GPCR?
Prevents efficient interaction of G-proteins with the ligand-bound receptor
This leads to desensitization of the receptor.
How do GRKs contribute to GPCR desensitization?
Phosphorylate ligand/agonist bound GPCRs at serine and threonine residues
They can be recruited to the cell membrane via interactions with activated βγ subunits.
What do arrestins do in GPCR desensitization?
Sterically uncouple trimeric G-protein from receptor and serve as scaffolding proteins
They increase the affinity for β-arrestin, facilitating internalization.
What is homologous desensitization?
A two-phase process involving receptor desensitization and down-regulation
Phase 1 occurs soon after agonist stimulation, while Phase 2 involves internalization.
What happens when GPCR signaling desensitization is dysregulated?
It can lead to pathological challenges such as angioedema
Dysregulation affects vascular permeability.
What animal model is used to study endothelial-specific GRK2 knockouts?
Tie2-CRE/GRK2 fl+/fl- mice
These mice exhibit altered GRK2 levels in endothelial cells.
What was the conclusion regarding GRK2 levels in angioedema patients?
Reduced GRK2 levels correlate with severe phenotype of angioedema
This establishes GRK2 as a regulator of BK signaling.
What happens to mice lacking β-arrestin?
Cardiac β1-AR becomes supersensitive, enhancing heart muscle contractile response
This indicates the role of β-arrestin in normal GPCR function.
What occurs during resensitization of GPCRs?
Recycling of receptors back to the membrane
This process is not common and is a form of GPCR regulation.
What is cell supersensitization in the context of GPCRs?
Cell increases GPCR expression when ligand levels are low
This occurs as a compensatory mechanism.
What is the effect of β-blockers on GPCR signaling?
They make the body think there is very little actual ligand around
This can lead to increased sensitivity upon withdrawal.
What is the role of β-blockers in relation to β-adrenergic receptors?
β-blockers block the ability of ligands to bind to β-adrenergic receptors (βARs)
This leads to an increase in the production of more receptors due to perceived low levels of ligand.
What is the recommended method for discontinuing β-blockers?
Gradual withdrawal is better than sudden withdrawal (cold turkey)
Sudden withdrawal can lead to increased sympathetic stimulation of the heart, increased heart rate, and angina pectoris.
What happens to βARs when a person discontinues β-blockers?
There are too many receptors for endogenous ligand to bind to
This occurs due to the body producing more receptors in response to the blocked binding of adrenaline.
What is desensitization in the context of GPCRs?
Desensitization may be an adaptive response to activating the GPCR, but can lead to pathological loss of receptor signaling.
What is the significance of GRK2 expression in heart failure?
GRK2 expression and activity are increased in human heart failure
It has been implicated in βAR desensitization and compromised cardiac function.
What is a novel early marker for cardiac dysfunction?
Elevation of GRK2 often precedes the development of clinical heart failure.
What does GRK2/βARK1 stand for?
Beta adrenergic receptor kinase 1.
How does compromised βAR signaling affect cardiac function?
Impaired βAR signaling compromises cardiac sensitivity to inotropic stimulation.
What mechanism leads to βAR uncoupling during CABG?
Increased GRK2 activity is the primary mechanism of βAR uncoupling during coronary artery bypass grafting (CABG).
What is the relationship between GRK2 activity and hypertension?
Transgenic mice with vascular smooth muscle-targeted overexpression of GRK2 showed elevated resting blood pressure.
What is a potential therapeutic target to prevent compromised heart function?
GRK2 inhibitor peptide may serve as a therapeutic target
It binds but has no catalytic activity, thus not phosphorylating GPCRs.
What is the effect of the C-terminal domain of GRK2 when transgenically expressed?
It improves cardiac performance by inhibiting GRK2’s ability to phosphorylate ligand-bound βARs.
What is Oguchi disease?
A rare autosomal recessive form of congenital stationary night blindness
It is linked to mutations in arrestin and GRK1.
What is the function of GRK1 (Rhodopsin kinase) in humans?
It is a rod-specific cytosolic enzyme that phosphorylates multiple serine residues on photoactivated rhodopsin GPCR.
True or False: Increased GRK2 activity is beneficial for heart function.
False
Too much GRK2 activity contributes to a hypertensive state.
Fill in the blank: Proper regulation of _______ is important for heart function.
βAR signaling.
